Autoamplification of NFATc1 expression determines its essential role in bone homeostasis

DOI PDF 被引用文献84件
  • Masataka Asagiri
    1Department of Cell Signaling, Graduate School
  • Kojiro Sato
    1Department of Cell Signaling, Graduate School
  • Takako Usami
    7Laboratory of Recombinant Animals, Medical Research Institute, Tokyo Medical and Dental University, Tokyo 101-0062, Japan
  • Sae Ochi
    1Department of Cell Signaling, Graduate School
  • Hiroshi Nishina
    8Department of Developmental and Regenerative Biology, Medical Research Institute, Tokyo Medical and Dental University, Tokyo 101-0062, Japan
  • Hiroki Yoshida
    6Precursory Research for Embryonic Science and Technology, Japan Science and Technology Agency, Kawaguchi, Saitama 332-0012, Japan
  • Ikuo Morita
    3Department of Cellular Physiological Chemistry, Graduate School
  • Erwin F. Wagner
    10Research Institute of Molecular Pathology, A-1030 Vienna, Austria
  • Tak W. Mak
    11Ontario Cancer Institute, Princess Margaret Hospital, Toronto, Ontario M5G 2M9, Canada
  • Edgar Serfling
    13Department of Molecular Pathology, Institute of Pathology, University of Wüerzburg, D-97080 Wüerzburg, Germany
  • Hiroshi Takayanagi
    1Department of Cell Signaling, Graduate School

抄録

<jats:p>NFATc1 and NFATc2 are functionally redundant in the immune system, but it was suggested that NFATc1 is required exclusively for differentiation of osteoclasts in the skeletal system. Here we provide genetic evidence that NFATc1 is essential for osteoclast differentiation in vivo by adoptive transfer of NFATc1−/− hematopoietic stem cells to osteoclast-deficient Fos−/− mice, and by Fos−/− blastocyst complementation, thus avoiding the embryonic lethality of NFATc1−/− mice. However, in vitro osteoclastogenesis in NFATc1-deficient cells was rescued by ectopic expression of NFATc2. The discrepancy between the in vivo essential role of NFATc1 and the in vitro effect of NFATc2 was attributed to selective autoregulation of the NFATc1 gene by NFAT through its promoter region. This suggested that an epigenetic mechanism contributes to the essential function of NFATc1 in cell lineage commitment. Thus, this study establishes that NFATc1 represents a potential therapeutic target for bone disease and reveals a mechanism that underlies the essential role of NFATc1 in bone homeostasis.</jats:p>

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